Personally, I hate to wait for water and I like redundancy, so I plan on multiple water heaters - not quite all POU, but if the plumbing isn't all centrally located, POU at far-end bathrooms definitely. Direct vent or normal would depend more on the installation - if you can direct vent, great, it'll save you on the venting and reduce connections, which reduces the possibility of leaks. But, you'll need to watch the clearances and if you're in an area prone to really hard freezes, check with a local installer who deals with these a lot and/or the manufacturer of the units you're considering as there's preventative measures you'll need to make sure you have in place to protect your heater (the heater equivalent of a backflow preventer, essentially, if it doesn't have built in protection for this).

We just purchased a large new home and it has 2- 50 gallon water heaters in the garage (gas). One is for the main house (2750 sq ft) and the other is for the granny flat above the garage that is 510 sq ft. I was surprise to see that both are 50 gallons! There are separate water meters. We haven't moved into the large house yet but the granny flat is rented and so far, all is good.